Hypertension (HTN), a disease that affects over 65 million Americans, is one of the most common chronic diseases in the world. Hypertensive heart disease (HHD) phenotypes, including left ventricular (LV) hypertrophy (LVH), LV diastolic dysfunction (LVDD), LV systolic dysfunction (LVSD), and vascular hypertrophy are common and inter-related. Furthermore, HHD-endophenotypes are commonly worsened by co-morbid conditions such as diabetes, obesity, metabolic syndrome, and dyslipidemia, thus suggesting that common underlying pathologic processes control/modulate these phenotypes through gene-gene (GxG) and/or gene-environment (GxE) interactions. During the first 5 years of this project, the investigative team has identified genes involved in myocardial metabolism and inflammation as putative modulators of these highly complex HHD-related phenotypes. The overarching hypothesis of this study is that in HTN, metabolic-inflammatory gene pathways interact to develop HHD-endophenotypes. This hypothesis will be tested by conducting a phenotype-genotype clinical study in 1,650 unrelated Caucasians by performing a high-density genome-wide association (GWA) study where single nucleotide polymorphisms (SNPs) will be associated with quantitative HHD-endophenotypes. The existing DNA repository includes exquisite, quantitative cardiovascular, metabolic, environmental, and inflammatory phenotypes ideal for association studies of the genetic/molecular basis of HTN/HHD-endophenotypes. The hypothesis is supported by studies in animal models of HHD conducted by collaborators at our institution and others. We have assembled a multidisciplinary team with expertise in clinical/translational research, molecular cardiology, and statistical genetics/genetic epidemiology, and build upon an existing comprehensive repository of DNAs and arrays of exquisite clinical phenotypes in 1000 Caucasian subjects. The revised specific aims (SA) for this two-year project are SA1. Enhance existing study cohort of 1,000 subjects by recruiting and phenotyping an additional 300 subjects to achieve a study population of 1,300 Caucasians. SA2. Perform integrated GWA analysis to develop a global survey of SNPs in pathways relevant for the development of HHD-endophenotypes in the Caucasian cohort. Exploratory Specific Aim. Select 2 top-ranked interacting candidate genes, one from each network, for fine-mapping of HHD variants by deep resequencing. GWA data from the primary and validation studies will lead to the construction of an HHD-pathways resource database. This research will result in a clear understanding of HHD and will generate the first database of highly dense SNP genotypes augmented by pathway information for future studies of HTN/HHD-endophenotypes.